Understanding the genetic factors underlying HD provides a powerful approach to identifying points of therapeutic intervention. The goals of the Genetics Core are therefore to use molecular techniques, in conjunction with each of the other Cores and projects in the program, to quantify the known genetic factor, CAG repeat length, that influences the onset and course of HD and to identify unknown genetic factors that influence HD and that cause related disorders. These goals will be met through three specific aims. In specific Aim # 1, we propose to provide clinical genetic testing for HD and similar disorders caused by CAG repeat expansions. There results will be used in every clinical study of the program. In addition, we will assist project with genetic mapping, sequence analysis, and other molecular techniques. In Specific Aim # 2, we will determine if genetic factors other than the CAG repeat in the HD gene influence HD onset on progression. Results will be confirmed by biochemical means, mouse models and through genetic studies of subjects from our collaborators. In Specific Aim # 3, we will identify novel causative mutations of familial disorders similar to HD. DNA from affected subjects found to have an HD-like phenotype and determined in Specific Aim # 1 to have none of the known CAG repeat expansions, will be assayed for the presence of a novel CAG repeat expansion. Any such expansion will be cloned. Genotype-phenotype relationships will be studied and the mutation will be studied. Overall, the proposed studies will facilitate every project of the program, and lead to new approaches for determining diagnosis, prognosis, and treatment of HD and related disorders.